It has become apparent that conditioning of drug effects to cues associated with cocaine and other psychomotor stimulants plays a very critical role in the development and maintenance of drug-induced sensitization, as well as the addictive processes related to these pharmacological agents. One aim of this research program was to define further the neuropharmacological and neuroanatomical substrates underlying those conditioned effects and to characterize the behavioral variables involved in their acquisition, retention, and extinction. In addition to its euphorogenic actions, cocaine also has anxiogenic properties. We have previously found that environmental cues associated with cocaine can elicit long-lasting anxiogenic-like actions that are reversed by pretreatment with the CRF antagonist alpha-helical-CRF. Cocaine-associated cues were also found to elicit conditioned release of plasma corticosterone (CORT), suggesting that some of the conditioned effects of cocaine involve activation of the HPA axis. Such conditioned endocrine effects were also antagonized by alpha-helical- CRF, again implicating CRF involvement. Amphetamine, morphine, nicotine, ethanol, and MK-801 (a noncompetitive NMDA antagonist) were found to increase plasma CORT in a dose-dependent fashion. Only amphetamine, however, was able to produce conditioned increases in CORT. Depletion of brain serotonin (5-HT) with 57-DHT had no effect on cocaine-induced increases in CORT, indicating that serotonergic pathways are probably not involved in the unconditioned or conditioned effects of cocaine on HPA axis activity. Pretreatment of rats with eticlopride (a D2 dopamine antagonist) and SCH 23310 (a D1 dopamine antagonist) prior to a series of extinction sessions prevented the expression of cocaine-conditioned behaviors, but had no effect on the extinction process. The antagonists by themselves produced no conditioned effects. Apomorphine (a direct DA agonist) also prevented extinction. Cues associated with cocaine were found to increase glucose utilization in the medial frontal cortex, basolateral amygdala, core and shell of the n. accumbens, ventral tegmental area (VTA), and various thalamic nuclei. Increased expression of c-fos mRNA also was seen in the n. accumbens by cocaine-associated cues. Increased activity in these structures appears to be related to the expression of conditioned cocaine effects and may underlie the incentive motivational processes responsible for craving.A second focus of this project has been on defining the neurobiological substrates underlying the actions of glutamate antagonists such as MK-801 and PCP, which are known to induce schizophrenic-like symptoms in man. A series of studies utilizing microdialysis, micro injection, and lesioning procedures evaluated the role of certain components of the basal ganglia circuits in mediating the effects of amphetamine, apomorphine, and MK-801. The findings indicate that while the locomotor stimulatory effects of dopamine agonists are dependent upon intact dopamine and involve GABAergic efferents from the n. accumbens to the ventral pallidum, MK- 801s stimulatory actions are independent of such mechanisms and may be more global in nature. In fact, micro injections of MK-801 into the n. accumbens, frontal cortex, medial thalamus, VTA, and subthalamic nucleus were all effective in producing increases in locomotor activity. - cocaine sensitization, plasma corticosterone (CORT), conditioned cues, CRF